The cotton-top tamarin (Saguinus oedipus) exhibits limited major histocompatibility complex (MHC) class I polymorphism and sequence variation, and is susceptible to viral infections. We infected three cotton-top tamarins with the influenza strain A/X-31 to explore the relationship between this primate's limited MHC class I diversity, and its susceptibility to viral infections. Influenza-specific, CD8+ cytotoxic T lymphocyte (CTL) lines derived from the three most MHC class I disparate animals in our colony killed influenza-infected allogeneic target cells derived from each other and from the bare-faced tamarin (Saguinus geoffroyi). An identical pattern of killing was observed using targets infected with a recombinant vaccinia construct expressing the influenza A nucleoprotein (NP). This NP-specific response was mapped to a 20 amino acid region at the C-terminal end of the NP molecule. Furthermore, this peptide was recognized on the surface of a human cell line expressing the cotton-top tamarin Saoe-G*08 allele. This allele is shared by all cotton-top tamarins and bare-faced tamarins. These observations suggest that epitope sharing, as a consequence of limited MHC class I diversity, may contribute to the cotton-top tamarins' unusual susceptibility to viral infections. Key Words MHC, Cotton-top tamarin, flu virus, CTL